The purpose of this research program is to elucidate the mechanisms of vaccine-induced immunity in schistosomiasis and to dissect the process of egg-induced granuloma formation. Several murine models of schistosomiasis are employed in these studies so that basic pathogenic processes can be investigated. Key findings in the murine studies are then extended to the field, where the immune responses of schistosomiasis patients exhibiting different clinical forms of the disease are examined. The ultimate goal of this research is to understand the host immune response to infection so that immunologically based strategies might be employed in the development of a highly effective vaccine for schistosomiasis. Progress was achieved in the following areas during the year: 1) The role of IL-10 in the regulation of egg-induced immunopathology during infection with S. mansoni was examined. Interleukin-10 gene knockout mice (IL-10T) were used to examine the role of endogenous IL-10 in the down-modulation of hepatic granuloma formation and lymphocyte response that occurs in chronic schistosomiasis infection. These studies showed that while IL-10 plays an important role in controlling acute granulomatous inflammation and the magnitude of the cytokine response, it plays no essential role in the process of immune down-modulation in chronic schistosome infection. 2) IL-10 was shown to play an important role in the suppression of Type-1 (IFN-&#61543;) cytokine expression in both acutely and chronically infected schistosomiasis patients. The contribution of IL-10 and IFN-&#61543; to the regulation of Type 1 and Type 2 cytokine responses was investigated in whole blood cultures obtained from Brazilian individuals with acute schistosomiasis or chronic intestinal disease and in the PBMCs and spleen cells of patients with hepatosplenic disease. These studies demonstrated that early or acute infection with S. mansoni is associated with a significant IFN-&#61543; response and that IL-10 contributes to the suppression of that response during both early and late infection. 3) IFN-&#61543;, IL-12, and TNF-&#61543; were shown to play key roles in the suppression of egg-induced liver pathology in mice vaccinated with egg antigens and IL-12. Severe pathology in schistosomiasis has been linked to a dominant CD4+ Th2-type cytokine response and our previous studies showed that sensitizing animals to egg antigens in combination with IL-12, prior to infection, leads to a highly significant reduction in egg-induced immunopathology. In this study, we demonstrated that in contrast to egg/IL-12- sensitized animals which showed marked decreases in pathology, mice similarly sensitized but depleted of IFN-&#61543;, IL-12, and TNF- &#61537; at the time of egg laying developed granulomas which were similar to the non-IL-12-treated control group. The mice also displayed a partial reduction in IFN-&#61543; production, which suggests that multiple Th1-associated cytokines may be required to maintain polarized Th1 responses in vivo. 4) IL-13 was identified as a key effector cytokine for granuloma formation. In this study, we showed that in vivo blockade of the Th2 cytokine IL-13, using sIL-13Ra2-Fc, significantly reduced the size of pulmonary granulomas in un-sensitized as well as egg- sensitized mice. Blocking IL-13 also significantly reduced total serum IgE levels. These findings suggest that IL-13 may play a central role in the development of egg-induced immunopathology. 5) The role of inducible nitric oxide-synthase in the regulation of immunity induced by attenuated cercariae of S. mansoni was examined. Inducible nitric oxide synthase-deficient mice were shown to develop an enhanced Type-1 cellular and humoral immune response after vaccination with attenuated S. mansoni cercariae but nevertheless, displayed a partial reduction in resistance.